Synthesis of 2,5-disubstituted furans via palladium-catalyzed annulation of alkyl 3-oxo-6-heptynoates

The reaction of the readily available alkyl 3-oxo-6-heptynoates with aryl halides in the presence of K2CO3 and catalytic amounts of Pd(PPh3)(4) at 100 degrees C provides a valuable new route to 2,5-disubstituted furans 3. Most probably, the furan ring is generated through an annulation reaction promoted by sigma-arylpalladium complexes generated in situ and involving the nucleophilic attack of the ketonic oxygen across the carbon-carbon triple bond coordinated to palladium, followed by the base-catalyzed isomerization of the resultant stereoisomeric 2,5-dialkylidenetetrahydrofuran intermediates 4 and 5. The reaction is highly chemoselective. No evidence was obtained of carboannulation products. The reaction temperature has proven to be crucial for the success of the methodology. The K2CO3:alkyne ratio also affects the reaction outcome. The highest yields of furan derivatives have been obtained with aryl halides containing electron-withdrawing substituents, very likely because the higher acidity of the methylene protons of 4 and 5 favors the isomerization step. Extension of the methodology to methyl 3-oxo-7-substituted-6-heptynoates leads to the formation of 2,5-disubstituted furans containing a branched side chain. The presence of an alkyl substituent on the C-2 of the staring alkyne, however, seems to prevent the isomerization step. Treatment of ethyl 2-methyl-3-oxo-6-heptynoate under our standard conditions produced in fact the 2,5-dialkylidene derivative 5p in 42% yield, and no evidence of the corresponding furan derivative was attained.